CN1198161A - Active oxygen scavengers containing pterin derivatives - Google Patents

Active oxygen scavengers containing pterin derivatives Download PDF

Info

Publication number
CN1198161A
CN1198161A CN97191002A CN97191002A CN1198161A CN 1198161 A CN1198161 A CN 1198161A CN 97191002 A CN97191002 A CN 97191002A CN 97191002 A CN97191002 A CN 97191002A CN 1198161 A CN1198161 A CN 1198161A
Authority
CN
China
Prior art keywords
active oxygen
formula
pterin
salt
record
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN97191002A
Other languages
Chinese (zh)
Other versions
CN1084332C (en
Inventor
荒井俊之
牧野圭佑
森健次郎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CMIC Co Ltd
Original Assignee
Artemis Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Artemis Inc filed Critical Artemis Inc
Publication of CN1198161A publication Critical patent/CN1198161A/en
Application granted granted Critical
Publication of CN1084332C publication Critical patent/CN1084332C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
  • Toxicology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

An active oxygen scavenger comprising a pterin derivative of the formula (I) as an active ingredient: wherein R1 and R2 are independently a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, or an acyl group of the formula R3-CO-, R3 is an alkyl group of 1 to 4 carbon atoms, X is a formyl group or hydroxymethyl group, A is a group of the formula (Ia): and n is 0 or an integer of 1 or more, when X is a hydroxymethyl group, n is 0, or when n is an integer of 1 or more, each of R1 and R2 is a hydrogen atoms, and X is a formyl group, or a cyclic compound thereof, or a salt thereof is disclosed.

Description

The active oxygen eliminating agent that contains pterin derivatives
Technical field
The present invention relates to contain the active oxygen eliminating agent of pterin derivatives.In addition, the invention still further relates to pharmaceutical composition or the make-up composition that contains above-mentioned pterin derivatives.
Background technology
For a long time, people just know and manyly think and the active oxygen diseases associated.As the example of these diseases, ischemic injuries (for example ischemic heart disease sequela, cerebral infarction sequela or stress ulcer), reperfusion injury, diseases associated with inflammation (for example chronic rheumatoid, ephritis or asthma), cancer, diabetes, cataract, arteriosclerosis, drug intoxication, pesticide intoxication, the liver injury that excessive administration causes, liver injury, premature infant's nethike embrane disease, photoallergy or the radiation damage etc. of agricultural chemicals excess ingestion are arranged.
For this treatment of diseases, give and enzyme with active oxygen elimination effect, effective as superoxide dismutase (hereinafter referred to as SOD).But the biological half-life of SOD is extremely short, essential a large amount of administrations.In addition,, have antigenicity, must consider the side effects such as anaphylactic shock that cause because of antigen antibody reaction in the time of must long term administration because enzyme is protein.Also have variety of problems such as oral administration is invalid.
As the non-protein compound that active oxygen is had the elimination effect, known have a pterin derivatives.For example, open in the flat 6-56669 communique, put down in writing pterin derivatives or neopterin derivative and had active oxygen elimination effect the spy.In addition, the spy opens and has put down in writing pterin derivatives same as described above in the flat 7-188232 communique or the neopterin derivative is effective to the cell injury that free radical causes.
As the neopterin of the representation compound of above-mentioned pterin derivatives or neopterin derivative (be 2-amino-4-oxygen-6-(D-is red-1 ', 2 ', 3 '-three hydroxypropyls)-pteridine; Be called for short NP) material that produces for scavenger cell, incomplete its physiological significance of understanding also at present, but known its for active oxygen Wheat Protein (S.Kojima etc. for example, FEBS, 304,2,3,163-166,1992; S.Kojima etc., FEBS, 329,1,2,125-128,1993).
In addition, be equivalent to 5,6,7 of reduced form neopterin, 8-tetrahydrochysene neopterin (is called for short NPH 4) knownly have a powerful antioxygenation, have report its to various diseases effectively (S.Kojima etc. for example, FEBS, 304,2,3,163-166,1992; Icho etc., Biochimical Pharmacology, 45,10,1953-1958,1993; Arai etc., Neuroscience Letters, 173 (1994) 107-110).
Yet, above-mentioned 5,6,7,8-tetrahydrochysene mopterin (NPH 4) have teratogenecity, therefore to seek the non-protein compound that other has active oxygen elimination effect.
The inventor furthers investigate the non-protein compound with active oxygen elimination effect, finds that the pterin derivatives that complete the unknown has an active oxygen elimination effect demonstrates active oxygen elimination effect.The present invention just is being based on this understanding.
Disclosure of an invention
According to the present invention, above-mentioned purpose can be that the active oxygen eliminating agent of feature reaches as effective constituent by adopting to contain the pterin derivatives shown in the formula (I), its ring or salt: R in the formula (1) 1And R 2The alkyl of representing hydrogen atom, carbon number 1～4 respectively independently, or formula R 3Acyl group shown in the-CO-, R 3Alkyl for carbon number 1～4; X is formyl radical or methylol; A is formula (Ia): Shown group, n are the integer more than 0 or 1; N was 0 when X was methylol; R when n is 1 above integer 1And R 2Be respectively hydrogen atom, X is a formyl radical.
In addition, the present invention also relates to pharmaceutical composition, it is characterized in that containing the salt of the pterin derivatives shown in the above-mentioned formula (I) or its ring or pharmaceutics permission as effective constituent.
Further, the present invention also relates to make-up composition, it is characterized in that containing the pterin derivatives shown in the above-mentioned formula (I), its ring or salt as effective constituent.
The simple declaration of accompanying drawing
Fig. 1 is for representing the figure of 6-formyl pterin eliminate activity oxygen activity with active oxygen accumulation luminous quantity in the PMN-PMA system.
The figure of the cryotronics spin resonance method measurement result when Fig. 2 adds 6-formyl pterin for the potassium superoxide solution of expression in DMSO.
Fig. 3 is not for carrying out the Photomicrograph of bloodstream blocking, fully normal sand mouse cerebral hippocampal tissue slice.
Fig. 4 is the Photomicrograph of cerebral hippocampal tissue slice of the control group of sand mouse-transient cerebral ischemia model.
Fig. 5 is the Photomicrograph of cerebral hippocampal tissue slice of the 6-formyl pterin administration group of sand mouse-transient cerebral ischemia model.
The optimised form that carries out an invention
Below the present invention is described in detail.
Active oxygen eliminating agent of the present invention contains the pterin derivatives of above-mentioned formula (I) expression as having The effect composition.
R 1、R 2And R3The alkyl of the carbon number 1～4 of expression is the alkane of the carbon number 1～4 of straight or branched Base, for example be methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or The tert-butyl group, preferable methyl or ethyl. In the compound shown in the above-mentioned formula (I), R1And R2Identical or different hydrogen atom can be represented respectively independently, the alkyl of above-mentioned carbon number 1～4, or formula R3-CO-(R 3Alkyl for above-mentioned carbon number 1～4) acyl group of expression. In the above-mentioned formula (I), n is Integer more than 0 or 1, preferred 0 or 1～100 integer, more preferably 0 or 1～10 integer.
As the pterin derivatives shown in the above-mentioned formula (I), preferred R 1And R 2The alkyl or the formula R that represent hydrogen atom, carbon number 1～4 respectively independently 3The group that-CO-represents, R 3Be the alkyl of carbon number 1～4, A is the group of formula (Ia) expression, and n is the integer more than 0 or 1, and X is the 6-formyl pterin derivatives of formyl radical.
Further, as the pterin derivatives shown in the above-mentioned formula (I), more preferably R 1And R 2Be hydrogen atom, and n is the compound shown in 0 the above-mentioned formula (I), i.e. formula (II): The 6-formyl pterin of expression.
6-formyl pterin is owing to have amino and formyl radical, and a plurality of intermolecular meeting natures form Schiff's base in the aqueous solution, thereby become oligopolymer or the polymer of 6-formyl pterin.In these oligopolymer or polymer, straight catenate oligopolymer or polymer are not only arranged, also contain cyclic oligopolymer or polymer.From the monomer to the oligopolymer or the reaction of polymer be reversible reaction, under alkaline condition, 6-formyl pterin oligopolymer or polymer resolve into 6-formyl pterin monomer easily.Therefore, can think and in body He on the skin, also can carry out same reversible reaction.Above-mentioned 6-formyl pterin oligopolymer or polymer are R 1And R 2Be hydrogen atom simultaneously, and n is compound shown in the above-mentioned formula (I) of the integer of (preferred 1～100) more than 1, can be used as the effective constituent in the active oxygen eliminating agent of the present invention and use.
Change the derivative of pterin derivatives shown in the above-mentioned formula (I) in body easily into, i.e. prodrug also can be used as effective constituent of the present invention and uses.The suitably selection of prodrug and the general method of preparation, for example at Design of Prodrugs, ed.H.Bundgaard, Elsevier has record on 1985.
6-formyl pterin can be used as effective constituent with the form of free cpds, also can be with its salt, the salt that allows of pharmaceutics particularly, for example the form of inorganic acid salt (for example hydrochloride or vitriol) or organic acid salt (for example camsilate, tartrate, malate or oxalate etc.) is used.In addition, also can use with the form of above-mentioned 6-formyl pterin oligopolymer or polymer.6-formyl pterin oligopolymer or polymer are compound known, and the known method according to himself can change salify from free cpds, also can be transformed into free cpds or other salt from salt.
Pterin derivatives shown in the above-mentioned formula (I) also can use as effective constituent with the form of free cpds, also can be with its salt, the particularly salt of pharmaceutics permission, for example the form of inorganic acid salt (for example hydrochloride or vitriol) or organic acid salt (for example camsilate, tartrate, malate or oxalate etc.) is used.Pterin derivatives shown in the above-mentioned formula (I) is a known compound, can be prepared with himself known method.In addition,, can change salify, also can be transformed into free cpds from salt from free cpds according to himself known method.
The salt that pterin derivatives shown in the above-mentioned formula (I) or its ring or pharmaceutics allow, because having active oxygen elimination effect maybe can change the compound with active oxygen elimination effect into, therefore can be used as the effective constituent of pharmaceutical composition of the present invention.
Be that n is 0, and R among the pterin derivatives shown in the above-mentioned formula (I) 1Or R 2Any be not that the pterin derivatives of formula (I) expression of hydrogen atom or 6-formyl pterin (are that n is 0, and R 1And R 2Be hydrogen atom simultaneously, X is the compound shown in the formula (I) of formyl radical) owing to himself have active oxygen elimination effect, the kind of active oxygen generation structure no matter, all the active oxygen that various reasons is produced has effectiveness widely.
In addition, in the pterin derivatives shown in the above-mentioned formula (I), n is that integer, the particularly n more than 1 is the pterin derivatives shown in the formula (I) of 1～100 integer, since after the administration in the body of animal or body surface slowly decompose, discharge 6-formyl pterin, the kind of active oxygen generation structure no matter, all the active oxygen that various reasons is produced has effectiveness widely.
So, pharmaceutical composition of the present invention can be relevant with free radical to active oxygen all diseases, for example ischemia injury (for example ischemic heart disease sequela, cerebral infarction sequela or stress ulcer), reperfusion injury, diseases associated with inflammation (for example chronic rheumatoid, ephritis or asthma), cancer, diabetes, cataract, arteriosclerosis, drug intoxication, pesticide intoxication, drug overdose effectively treat or prevent for liver injury, premature infant's nethike embrane disease, photoallergy or the radiation damage etc. that cause with the liver injury that causes, agricultural chemicals excess ingestion.
According to pharmaceutical composition of the present invention, the salt that pterin derivatives or its pharmaceutics allow, can be separately or the general carrier that allows of preferred and pharmaceutics or veterinary science common to and animal, preferred mammal (particularly people).
As form of administration, have no particular limits, oral preparations such as powder, granula subtilis, granule, tablet, capsule, suspensoid, emulsion, lotion, syrup, extractum or pill are for example arranged, or injection, liquid for external use, ointment, suppository, local give with non-oral formulations such as emulsifiable paste, jelly, gelifying agent, paste or drop.
These oral preparations for example can be used gelatin, sodium alginate, starch, W-Gum, white sugar, lactose, glucose, mannitol, carboxymethyl cellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soybean lecithin, sucrose, fatty acid ester, talcum, Magnesium Stearate, polyoxyethylene glycol, Magnesium Silicate q-agent, anhydrous silicic acid, or the vehicle of synthetic aluminium silicate etc., wedding agent, disintegrating agent, tensio-active agent, lubricant, flow promoting agent, thinner, preservatives, tinting material, spices, correctives, stabilization agent, wetting Agent for Printing Inks, sanitas or antioxidant etc. are made according to well-established law.Capsule of 6-formyl pterin and lactose mixed filling etc. for example.
As non-oral administration method, topical, injection (subcutaneous, intravenously etc.) or rectal administration etc. with emulsifiable paste or ointment etc. are for example arranged.Among this, injection is only.
For example when the preparation of injection, except pterin derivatives, can use for example isotonization agent, solubilizing agent, stabilization agent, sanitas, outstanding turbidization agent or the emulsifying agent etc. of water-insoluble solvent such as water-soluble solvent such as physiological saline or ringer's solution, vegetables oil or fatty acid ester, glucose or sodium-chlor etc. arbitrarily as effective constituent.
In addition, pharmaceutical composition of the present invention also can adopt the slow-releasing preparation mode of slow-releasing polymer etc. to carry out administration.For example, in the poly ethylene vinyl acetate sheet of pharmaceutical composition of the present invention can being packed into, again this sheet is implanted in the tissue that will treat with surgical operation.
Pharmaceutical composition of the present invention is not limited only to these, and it can contain salt 0.01～99% weight of pterin derivatives or the permission of its pharmaceutics, preferred 0.1～80% weight.
The dosage of utilizing the active oxygen of pharmaceutical composition of the present invention to eliminate to do the time spent is different different because of the degree of kinds of Diseases, patient age, sex, body weight, symptom or medication etc., have no particular limits, can give suitable 6-formyl pterin 0.1～100mg/kg body weight, 1～4 time on the 1st oral or non-oral administration for the adult usually.
Because the salt that the pterin derivatives shown in the above-mentioned formula (I) or its ring bodies or pharmaceutics allow has the active oxygen elimination effect compound of tool active oxygen elimination effect of maybe can deriving, so can be used as the effective constituent of make-up composition.Skin is the outermost layer of body, is subjected to the influence of active oxygen because of environmental factors (particularly action of ultraviolet ray).The dermatosis that influence causes as active oxygen for example has inflammatory dermatosis, collagenosis, seborrheic keratosis, blister disease or photoallergy etc.Because the stratum corneum of skin has barrier function, effective constituent mainly only acts on epidermis when giving with external application agent shape such as makeup, and the restraint of for example known peroxidatic reaction of lipid to epidermis can be quite effective.So, make-up composition of the present invention can eliminate with the action of ultraviolet radiation be radioactive rays, nitrogen peroxide or the smoke from cigarette etc. of representative at the active oxygen that skin surface produces, can avoid, alleviate or skin injury that prophylactic activity oxygen causes.
In make-up composition of the present invention, the proportion of the pterin derivatives shown in the above-mentioned formula (I) or its ring bodies or salt does not have special restriction, can contain 0.01～99% weight, preferred 0.1～80% weight.
Make-up composition of the present invention can with other compositions of using in the general makeup, as oil content, antioxidant, tensio-active agent, wetting Agent for Printing Inks.Spices, water, alcohol, tackifier, sanitas, mould inhibitor, Bao Su, powder and/or medicament etc. carry out suitable compatibility.In addition, it also can be as required and UV light absorber as you know, for example benzoic acids UV light absorber (for example para-amino benzoic acid), anthranilic acid UV light absorber (for example same methyl-N-acetyl cinnamyl o-aminobenzoate), salicylic acid UV light absorber (for example orchidae), cinnamic acid UV light absorber (for example styracin monooctyl ester) and/or benzophenone UV light absorber (for example 2,4-dihydroxy benzophenone) etc. are used.
Make-up composition of the present invention can make solution, emulsion, coagulation shape mixture, solid substance (stampings), powder etc. are form arbitrarily, can utilize its to make Exposure to Sunlight makeup, anti-Exposure to Sunlight makeup, face powder at the bottom of, casting resin, astringent, foundation cream, emulsifiable paste, emulsion, shampoo, hair rinse, cosmetic hair etc.As previously mentioned, because of the excessive generation of the meeting of active oxygen in the presence of intensive ultraviolet, so Exposure to Sunlight makeup or anti-Exposure to Sunlight makeup that intensive ultraviolet uses down are preferred, for example solar oil, sun washing lotion, sun emulsifiable paste, anti-Exposure to Sunlight emulsifiable paste, anti-Exposure to Sunlight washing lotion, anti-Exposure to Sunlight with foundation cream, anti-Exposure to Sunlight with at the bottom of the face powder or anti-Exposure to Sunlight with mixture etc.
For 6-formyl pterin, when carrying out acute toxicity test,, observed 3 months the 6-formyl pterin of 10 rat intravenous injection 6mg/kg body weight with rat, do not see dead example.
The purposes of active oxygen eliminating agent of the present invention is not limited in medicine and makeup, other various purposes can be arranged, for example can be used as functional foodstuff or heath food with the form of beverage, food give with, more can be used as feed and give and non-human animal (particularly feeding animals), can be used as the additive that adds in the preservation liquid of organ transplantation with organ toward preserving in addition.
Embodiment
Followingly the present invention is made specific description, but the present invention is not construed as limiting according to embodiment.The mensuration (PMN-PMA system) of embodiment 1:6-formyl pterin active oxygen eliminate activity
Take 10 milliliters of venous blood of health adult, separate neutrophilic granulocyte (the polymorphonuclear leukocyte that takes; Be called for short PMN), outstanding turbid with HBSS (Hanks ' balanced saltsolution, Hand ' s balanced salt solution) into about 1 * 10 6The suspension liquid of cells/ml.With chemiluminescent substance (promptly when active oxygen exists, producing chemiluminescent compound) 2-methyl-6-phenyl-3,7-glyoxalidine-(1,2-α)-pyrazine-3-ketone (hereinafter referred to as CLA) is with phosphate buffer solution (hereinafter referred to as the PBS dissolving), makes the solution of 50 μ M.Can stimulate neutrophil leucocyte to produce so-called neutrophil leucocyte stimulant phorbol myristin acetic ester (the phorbol myri state acetate of active oxygen; Be called for short PMA) dissolve with PBS, make the solution of 20 mcg/ml.The neutrophil leucocyte suspension liquid, CLA solution and the PMA solution that prepare were like this all used ice-cooled preservation before measuring.
The effective constituent 6-formyl pterin of active oxygen eliminating agent of the present invention is dissolved with PBS, make the solution of 100 μ M, 250 μ M and 500 μ M, before measuring use, be warmed to 37 ℃.Meanwhile the PBS that will use in contrast also is warmed to 37 ℃ before measuring use.
Carry out in the following order during mensuration.Toward the 6-formyl pterin solution that adds various concentration from the neutrophil leucocyte of 2 milliliters of centrifugations of neutrophil leucocyte suspension liquid, and adding PBS, to adjust cumulative volume be 1930 microlitres, inserts test tube and heated under 37 ℃ 15 minutes.After adding 50 microlitre CLA solution, place the chemical luminescent detecting device, begin to measure the chemoluminescence amount.Measure beginning after 1 minute, go into PMA solution 20 microlitres with syringe continent in the test tube.Be determined at 37 ℃ and carried out once in per 10 seconds down, continue 10 minutes.
The result as shown in Figure 1.Figure among Fig. 1 represents that the each cumulative of per 10 seconds luminous quantity adds up to luminous quantity.Curve a represents control group, promptly replaces 6-formyl pterin, the measurement result when only adding PBS; Measurement result when curve b represents to add 100 μ M6-formyl pterins; Measurement result when curve c represents to add 250 μ M6-formyl pterins; Measurement result when curve d represents to add 500 μ M6-formyl pterins.Contrast when only adding PBS with replacement 6-formyl pterin (curve a) is compared, when adding 100 μ M6-formyl pterins (curve b), and the chemoluminescence amount, promptly the active oxygen amount is significantly suppressed; Further, when adding 250 μ M and 500 μ M 6-formyl pterins (curve c and curve d), the chemoluminescence amount, promptly the active oxygen amount almost disappears.The mensuration (deriving from potassium superoxide) of embodiment 2:6-formyl pterin active oxygen eliminate activity
In 20 milliliters of methyl-sulphoxides (DMSO), add potassium superoxide (KO 2) 28 milligrams, be mixed with saturated solution, so produce active oxygen among the DMSO.Use 2,2,6 here, 6-tetramethyl piperidine-N-oxide compound (TEMPO) is as reference material, and it is added among the DMSO respectively as 0.1,0.3,0.5,0.7,1,1.2 and the solution of 1.5mM, measures.Gained electron spin resonance signal (77K measures down) carries out integration, makes typical curve.According to this typical curve, record that the concentration of active oxygen is about 0.5mM among the DMSO.
The effective constituent 6-formyl pterin of active oxygen eliminating agent of the present invention is dissolved with DMSO, make the solution of 10mM.Measure above-mentioned KO with low temperature (77K) electron spin resonance 2Active oxygen generation (contrast) and above-mentioned KO when not adding 6-formyl pterin in the solution 2Active oxygen generation when solution adds predetermined concentration 6-formyl pterin.
Measurement result as shown in Figure 2.6-formyl pterin in DMSO ultimate density from 0.001mM to 1mM per 10 times when rising from KO 2The active oxygen generation can be from position shown in the arrow A, promptly peak shown in the position of 328mT (derivative-type) the big or small degree of carrying out the quadratic integral value of trying to achieve is obtained.Curve a is contrast, the measurement result when promptly not adding 6-formyl pterin; Measurement result when curve b～e represents respectively to add 0.001mM, 0.01mM, 0.1mM and 1mM 6-formyl pterin.
With the KO that does not add 6-formyl pterin 2Solution is compared, to KO 2Add 6-formyl pterin in the solution, 6-formyl pterin concentration reaches 0.1mM, KO 2The active oxygen amount that produces descends, and 6-formyl pterin concentration reaches 1mM, KO 2The active oxygen that produces almost disappears.
As what before confirmed, add 28 milligrams of KO among 20 milliliters of DMSO 2The active oxygen generation of system is about 0.5mM, and thinks that 6-formyl pterin approximately eliminates from KO with 1: 1 ratio 2The active oxygen that produces.Embodiment 3: the mensuration (deriving from potassium superoxide) of methylol body active oxygen eliminate activity
6-hydroxymethyl pterine (R in the above-mentioned formula (I) with 0.01mM～10mM 1And R 2For hydrogen atom, X are that methylol, n are 0 o'clock compound) replace the 6-formyl pterin of 0.001mM～1mM, outside this, repeat the foregoing description 2 same operation, measure the active oxygen eliminate activity of 6-hydroxymethyl pterine, can observe when having the active oxygen eliminate activity identical with 6-formyl pterin, 6-hydroxymethyl pterine concentration is 10 times of 6-formyl pterin.Embodiment 4: because of the inhibition of active oxygen elimination effect to tardy property neuronal necrosis
Sand mouse (about 80 grams of the body weight) neck of general anesthesia is cut, and direct-view is down with clip ligation two bilateral common carotid arteries, thus blocking blood flow.5 minutes logical again blood flows are sewed up wound portion.After blood flow poured into 30 minutes again, the control group abdominal cavity gave 1 milliliter in physiological saline, and administration group abdominal cavity awards 1 milliliter of 50mM 6-formyl pterin (being dissolved in physiological saline); 1 time-of-week is raised in animal awakening from anesthesia after this.After 1 week,, make tissue slice, to microtubule bindin 2 (the microtuble-associated protein2 of special description neurocyte with above-mentioned sand mouse general anesthesia extraction brain; MAP2) dye, estimate tardy property neuronal necrosis (the delyed neuronaldeath of cerebral hippocampal; DND) degree.
Fig. 3～Fig. 5 represents the microphotograph of above-mentioned sand mouse cerebral hippocampal tissue slice.Fig. 3 is the tissue slice photo of blocking blood flow, fully normal structural state not, and Fig. 4 is the tissue slice photo of control group, and Fig. 5 then is the photo of the tissue slice of 6-formyl pterin administration group.In addition, Fig. 3 (1), Fig. 4 (1) and Fig. 5 (1) are respectively and amplify 60 times photo, and Fig. 3 (2), Fig. 4 (2) and Fig. 5 (2) are respectively and amplify 600 times photo.
Fig. 4 demonstrates the state that neuronal cell comes off fully, and Fig. 5 demonstrates the state that many neuronal cells keep existence.
The above results shows, 6-formyl pterin is because of its active oxygen elimination effect, and can suppress the tardy property neuronal necrosis of sand mouse transient cerebral ischemia model.
Industrial applicibility
Active oxygen eliminating agent of the present invention is effective to the active oxygen that various reasons produces. So, contain The pharmaceutical composition of the present invention of above-mentioned active oxygen eliminating agent is expected can be to being considered to relevant with active oxygen Various diseases effectively treat. In addition, contain the of the present invention of above-mentioned active oxygen eliminating agent Cosmetic composition is expected to alleviate and to avoid the bad of the active oxygen that produces because of effects such as ultraviolet rays Impact.

Claims (11)

1. active oxygen eliminating agent is characterized in that containing the pterin derivatives shown in the formula (I) or its ring bodies or its salt as effective constituent: R in the formula (I) 1And R 2Represent hydrogen atom respectively independently, the alkyl of carbon number 1～4, or formula R 3Acyl group shown in the-CO-, R 3Alkyl for carbon number 1～4; X is formyl radical or methylol, and A is formula (Ia):
Figure A9719100200022
Shown group, n are the integer more than 0 or 1; N was 0 when X was methylol, R when n is 1 above integer 1And R 2Be respectively hydrogen atom, X is a formyl radical.
2. according to the active oxygen eliminating agent of claim 1 record, wherein contain the 6-formyl pterin shown in the formula (II) or its salt as effective constituent.
3. pharmaceutical composition is characterized in that containing salt that pterin derivatives, its ring bodies or the pharmaceutics shown in the formula (I) of claim 1 record allow as effective constituent.
4. according to the pharmaceutical composition of claim 3 record, be used for prevention and treatment with the active oxygen diseases related.
5. according to the pharmaceutical composition of claim 4 record, be liver injury, premature infant's nethike embrane disease, photoallergy, the radiation damage that ischemia injury, reperfusion injury, diseases associated with inflammation, cancer, diabetes, cataract, arteriosclerosis, drug intoxication, pesticide intoxication, the excessive liver injury that causes of drug administration, agricultural chemicals excess ingestion cause wherein with the active oxygen diseases associated.
6. make-up composition is characterized in that containing pterin derivatives or its ring bodies or the salt shown in the formula (I) of claim 1 record.
7. the functional foodstuff of treatment or prevention and active oxygen diseases related is characterized in that containing pterin derivatives or its ring bodies or the salt shown in the formula (I) of claim 1 record.
8. the feed of prevention or treatment and active oxygen diseases related is characterized in that containing pterin derivatives or its ring bodies or the salt shown in the formula (I) of claim 1 record.
9. organ preservative fluid additive is characterized in that containing pterin derivatives or its ring bodies or the salt shown in the formula (I) of claim 1 record.
10. with the prevention or the methods of treatment of active oxygen diseases related, comprising pterin derivatives or its ring bodies or the salt shown in the formula (I) that claim 1 is put down in writing, with the prevention and the significant quantity of therapeutic activity oxygen diseases related, to the object that must prevent or treat the active oxygen diseases related.
11. be used for the application that pharmaceutical composition is made according to the pterin derivatives shown in the formula (I) of claim 1 record or its ring bodies or salt.
CN97191002A 1996-07-31 1997-07-30 Active oxygen scavengers containing pterin derivatives Expired - Fee Related CN1084332C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP218043/96 1996-07-31
JP21804396 1996-07-31

Publications (2)

Publication Number Publication Date
CN1198161A true CN1198161A (en) 1998-11-04
CN1084332C CN1084332C (en) 2002-05-08

Family

ID=16713759

Family Applications (1)

Application Number Title Priority Date Filing Date
CN97191002A Expired - Fee Related CN1084332C (en) 1996-07-31 1997-07-30 Active oxygen scavengers containing pterin derivatives

Country Status (10)

Country Link
US (1) US6162806A (en)
EP (1) EP0884317B1 (en)
KR (1) KR19990063880A (en)
CN (1) CN1084332C (en)
AT (1) ATE295847T1 (en)
AU (1) AU739069B2 (en)
DE (1) DE69733308D1 (en)
IL (1) IL123884A (en)
NZ (1) NZ330078A (en)
WO (1) WO1998004558A1 (en)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69920757T2 (en) * 1998-12-28 2005-12-15 4 AZA Bioscience N.V. IMMUNOSUPPRESSIVE EFFECTS OF PTERIDINE DERIVATIVES
US7276506B2 (en) 1998-12-28 2007-10-02 4 Aza Bioscience Nv Immunosuppressive effects of pteridine derivatives
CA2545584C (en) 2003-11-17 2012-10-23 Biomarin Pharmaceutical Inc. Methods and compositions for the treatment of metabolic disorders
MX2007005039A (en) 2004-11-17 2007-06-19 Biomarin Pharm Inc Stable tablet formulation of tetrahydrobiopterin.
US9259426B2 (en) 2006-07-20 2016-02-16 Gilead Sciences, Inc. 4,6-di- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections
US10144736B2 (en) 2006-07-20 2018-12-04 Gilead Sciences, Inc. Substituted pteridines useful for the treatment and prevention of viral infections
JP2010515747A (en) * 2007-01-12 2010-05-13 ビオマリン プハルマセウトイカル インコーポレイテッド Tetrahydrobiopterin prodrug
KR100882340B1 (en) * 2007-03-30 2009-02-11 주식회사 래디안 Cosmetic composition comprising pterins stabilized in nanoliposome and manufacturing method thereof
BRPI0821970A2 (en) * 2008-01-03 2015-06-23 Biomarin Pharm Inc Pterine analogs for bh4 responsive condition treatment
WO2011159471A2 (en) * 2010-06-18 2011-12-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Linked purine pterin hppk inhibitors useful as antibacterial agents
US9216178B2 (en) 2011-11-02 2015-12-22 Biomarin Pharmaceutical Inc. Dry blend formulation of tetrahydrobiopterin
US10316167B2 (en) * 2014-09-19 2019-06-11 Plastipak Packaging Oxygen scavengers, compositions comprising the scavengers, and articles made from the compositions
SI3321265T1 (en) 2015-03-04 2020-07-31 Gilead Sciences, Inc. 4,6-diamino-pyrido(3,2-d)pyrimidine compounds and their utilisation as modulators of toll-like receptors
MA46093A (en) 2016-09-02 2021-05-19 Gilead Sciences Inc TOLL-TYPE RECEIVER MODULATING COMPOUNDS
US10640499B2 (en) 2016-09-02 2020-05-05 Gilead Sciences, Inc. Toll like receptor modulator compounds
WO2018071531A1 (en) 2016-10-11 2018-04-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Hppk inhibitors useful as antibacterial agents
TWI751516B (en) 2019-04-17 2022-01-01 美商基利科學股份有限公司 Solid forms of a toll-like receptor modulator
TW202212339A (en) 2019-04-17 2022-04-01 美商基利科學股份有限公司 Solid forms of a toll-like receptor modulator
TW202115056A (en) 2019-06-28 2021-04-16 美商基利科學股份有限公司 Processes for preparing toll-like receptor modulator compounds

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4994303A (en) * 1988-03-21 1991-02-19 Garlock, Inc. Fiber impregnation process
JPH0656669A (en) * 1992-06-11 1994-03-01 Asahi Breweries Ltd Pterine derivative preparation having active oxygen-scavenging action
DE4418096A1 (en) * 1994-05-24 1995-11-30 Cassella Ag Use of pteridine derivatives as inhibitors of NO synthase
ATE218345T1 (en) * 1994-08-05 2002-06-15 Suntory Ltd DRUGS FOR SPINOCEREBELLAR DEGENERATION
KR20060094988A (en) * 1996-08-30 2006-08-30 다이이치 아스비오파마 가부시키가이샤 Preventives or remedies for diseases induced by hypofunction of nitric oxide synthase (nos)

Also Published As

Publication number Publication date
CN1084332C (en) 2002-05-08
DE69733308D1 (en) 2005-06-23
US6162806A (en) 2000-12-19
IL123884A0 (en) 1998-10-30
AU3707197A (en) 1998-02-20
AU739069B2 (en) 2001-10-04
EP0884317B1 (en) 2005-05-18
NZ330078A (en) 2000-01-28
WO1998004558A1 (en) 1998-02-05
EP0884317A2 (en) 1998-12-16
EP0884317A4 (en) 1999-04-14
KR19990063880A (en) 1999-07-26
IL123884A (en) 2002-04-21
ATE295847T1 (en) 2005-06-15

Similar Documents

Publication Publication Date Title
CN1084332C (en) Active oxygen scavengers containing pterin derivatives
ES2344920T3 (en) PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF PATHOLOGIES CAUSED BY THE GENERAL RESPONSE OF THE IMMUTARY SYSTEM.
JPS62215527A (en) Alzheimer's sclerosis remedy
JP2011512366A (en) Folate, their composition and use
KR101563308B1 (en) Inclusion complexes of pinocembrin with cyclodextrin or its derivatives
CA2781436A1 (en) Arachidonic acid analogs and methods for analgesic treatment using same
TWI564291B (en) Agent for regulating the formation of nitrogen monoxide
JP6997995B2 (en) Phenolic compounds for the treatment of central nervous system and vasculature disorders and their combination with benzodiazepines fused to 1,4-dihydropyridine
JP2019112354A (en) Antiinflammatory agent and antiinflammatory composition
RU2485956C2 (en) New composition for treating side effects of anti-cancer therapy
KR101623682B1 (en) Pharmaceutical composition comprising eriodictyol or its pharmaceutically acceptable salts as an active ingredient for preventing or treating contact dermatitis
JPS6352012B2 (en)
CA3159633A1 (en) Mrgprx2 antagonists and uses thereof
US3852454A (en) Treatment of rheumatoid arthritis
RU2005113980A (en) STRENGTHENING ALCOHOL METABOLISM
JP2007326796A (en) Bleaching agent containing gold colloid and thyrosinase inhibitor
CN1285332C (en) Ginkgo keto-ester soft capsules with long stable effect and preparation thereof
KR100286141B1 (en) Pharmaceutical composition for the treatment of septic shock, antipyretic and anti-inflammatory, containing 6,7-substituted-2-aminotetraline
KR102690547B1 (en) Composition comprising N-trans-caffeoyltyramine for skin whitening and enhancing skin barrier
EP0429245B1 (en) A therapeutic agent for central nervous diseases
CN114853715B (en) Organic nitrite donor ketal type prodrug, preparation method and medical application thereof
ES2532479T3 (en) Agents for the treatment of migraine
JPH03287531A (en) Remedy for pacreatitis
JPH03501387A (en) Method of treating inflammation in mammals using ketobutyrolactone and furilbutyrolactone
Zhao et al. Composition containing artesunate

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
ASS Succession or assignment of patent right

Owner name: CMIC CO., LTD.

Free format text: FORMER OWNER: ARTEMIS INC.

Effective date: 20010707

C41 Transfer of patent application or patent right or utility model
TA01 Transfer of patent application right

Effective date of registration: 20010707

Applicant after: CMIC Co., Ltd.

Applicant before: Artemis Inc.

C14 Grant of patent or utility model
GR01 Patent grant
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee